EP1220840A2 - Amines bicyliques et tricycliques en tant que modulateurs de l'activite du recepteur de chemokine - Google Patents

Amines bicyliques et tricycliques en tant que modulateurs de l'activite du recepteur de chemokine

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Publication number
EP1220840A2
EP1220840A2 EP00973508A EP00973508A EP1220840A2 EP 1220840 A2 EP1220840 A2 EP 1220840A2 EP 00973508 A EP00973508 A EP 00973508A EP 00973508 A EP00973508 A EP 00973508A EP 1220840 A2 EP1220840 A2 EP 1220840A2
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European Patent Office
Prior art keywords
chr
alkyl
substituted
occurrence
alkynyl
Prior art date
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EP00973508A
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German (de)
English (en)
Inventor
Dean A. Wacker
John V. Duncia
Joseph B. Santella Iii
Daniel S. Gardner
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Bristol Myers Squibb Pharma Co
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Bristol Myers Squibb Pharma Co
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Publication of EP1220840A2 publication Critical patent/EP1220840A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems

Definitions

  • This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)).
  • CXC chemotactic cytokines
  • CC chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)).
  • CXC single amino acid
  • CC adjacent
  • the CXC chemokines such as interleukin-8 (IL-8) , neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MlP-l ⁇ , MlP-l ⁇ , the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils.
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • lymphotactin-1 lymphotactin-1
  • lymphotactin-2 both C chemokines
  • fractalkine a CXXXC chemokine
  • chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed "chemokine receptors.”
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration.
  • CCR-1 or "CKR-1" or
  • CC-CKR-1 [MlP-l ⁇ , MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or "CKR- 2A”/"CKR-2B” or "CC-CKR-2A” / "CC-CKR-2B” ) [MCP-1, MCP-2 , MCP-3, MCP-4, MCP-5] (Charo et al . , Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J.
  • CCR-3 or "CKR-3” or "CC- CKR-3" [eotaxin-1, eotaxin-2 , RANTES, MCP-3, MCP-4] (Combadiere, et al . , J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));
  • CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MIP-l ⁇ , RANTES, MCP-1] (Power et al . , J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));
  • CCR-5 (or "CKR-5" OR “CC-CKR-5") [MlP-l ⁇ , RANTES, MIP- l ⁇ ] (Sanson, et al . , Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or “CC-CKR-6") [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or “CKR-7” or "CC-CKR-7” ) [ELC] (Yoshie et al . , J. Leukoc. Biol.
  • CCR-8 or "CKR-8” or "CC-CKR-8" [1-309, TARC, MlP-l ⁇ ] (Napolitano et al . , J. Immunol., 157, 2759-2763 (1996), Bernardini et al . , Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or “CKR- 10" or "CC-CKR-10") [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol. , 16, 1249-1256 (1997)).
  • mammalian cytomegaloviruses In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses , herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)).
  • Human CC chemokines such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection.
  • human chemokine receptors such as CXCR4, CCR2 , CCR3 , CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV) .
  • HAV human immunodeficiency viruses
  • Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells.
  • the chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses .
  • WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors :
  • Ri is C ⁇ _ 6 alkyl, optionally substituted with functional groups such as -NR 6 CONHR 7 , wherein R 6 and R 7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl .
  • Such spiro compounds are not considered part of the present invention.
  • WO 95/13069 is directed to certain piperidine, pyrrolidine, and hexahydro-lH-azepine compounds of general formula:
  • Z NRg a or 0.
  • WO 93/06108 discloses pyrrolobenzoxazine derivatives as 5-hydroxytryptamine (5-HT) agonists and antagonists :
  • A is lower alkylene and R 4 may be phenyl optionally substituted with halogen.
  • NPY neuropeptide sethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-dihydropyridinesethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-amino
  • B may be NH, NR 1 , O, or a bond
  • R 7 may be substituted phenyl, benzyl, phenethyl and the like.
  • one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof. It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • It is another object of the present invention to provide a method for treating inflammatory and allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • A, E, G and R 1 are defined below, are effective modulators of chemokine activity.
  • the present invention provides novel compounds of formula (I) : -NR 1 —G
  • A is selected from
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR 1:L R 12 )
  • ring D is selected from a C 3 - 6 carbocyclic residue and a 5 or 6 membered heterocycle
  • W at each occurrence, is independently selected from C or N, provided at least two of W are C;
  • X 1 and X 2 are independently selected from C and N;
  • Z 1 is selected from C and N;
  • Z 2 is selected from NR 1 ', O, S and C;
  • R 1 , R 1 ' and R 2 are independently selected from H, C ⁇ _ 8 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, (CH 2 ) r C 3 -6 cycloalkyl, and a (CH 2 ) r _ C 3 - lO carbocyclic residue substituted with 0-5 R a ;
  • R la is independently selected from H, C ⁇ _ 6 alkyl, -OH, CN, -N0 2 , (CH 2 ) r C3-6 cycloalkyl, and a (CH 2 ) r -C3- ⁇ o carbocyclic residue substituted with 0-5 R a ;
  • R b at each occurrence, is selected from H, C -Q alkyl, C 3 - 6 cycloalkyl, and phenyl;
  • R c at each occurrence, is selected from C 1 - 6 alkyl, C 3 - 6 cycloalkyl, and phenyl;
  • R 1 and R 2 join to form a 5, 6, or 7- membered ring substituted with 0-3 R a ;
  • R 3 is selected from a (CR 3 'R 3 ") r -C 3 _ ⁇ o carbocyclic residue substituted with 0-5 R 15 and a (CR 3 'R 3 ") r -5- 10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15 ;
  • R 3 ' and R 3 " are selected from H, C ⁇ _ 6 alkyl, (CH ) r C 3 - 6 cycloalkyl, and phenyl;
  • R 4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C ⁇ _ 8 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, (CH 2 ) r C 3 _ 6 cycloalkyl, (CH 2 ) g C (0) R 4b , (CH 2 ) q C (0)NR 4a R 4a ' , (CH ) q C(0)OR 4a , and a (CH 2 ) r -C 3 - ⁇ o carbocyclic residue substituted with 0-3 R 4c ;
  • R a and R a ' are selected from H, C ⁇ _ 6 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, and phenyl;
  • R b at each occurrence, is selected from C ⁇ - 6 alkyl, C2-8 alkenyl, (CH 2 ) r C 3 - 6 cycloalkyl, C2- 8 alkynyl, and phenyl;
  • R 4c at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 7 is selected from H, C ⁇ - 6 alkyl, C 2 - 8 alkenyl, C 2 - alkynyl, (CHR') q OH, (CHR') g SH, (CHR') q OR 7d ,
  • R 7a and R 7a ' are selected from H,
  • R 7b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 7d is selected from methyl, CF 3 , C 2 - 6 alkyl substituted with 0-3 R 7e , C 3 - 6 alkenyl, C 3 - 6 alkynyl, and a C 3 - 10 carbocyclic residue substituted with 0-3 R 7c ;
  • R 7e is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OCi- 5 alkyl, OH, SH, (CH 2 ) r SCi_ 5 alkyl, (CH 2 ) r NR 7f R 7f , and (CH 2 ) r phenyl;
  • R 7f at each occurrence, is selected from H, C 1 - 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 8 is selected from H, C ⁇ _ 6 alkyl, C 3 _ 6 cycloalkyl, and (CH 2 ) r nen Yl substituted with 0-3 R 8a ;
  • R 8a at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 8b is selected from H, C 1 - 6 alkyl, C 3 - 6 cycloalkyl, OH, CN, and (CH 2 ) r -phenyl ;
  • R 9 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, F, Cl, Br, I, N0 2 , CN, (CHR') r OH, (CHR') r SH, (CHR') r OR 9d , (CHR') r SR 9d , (CHR' ) r NR 9a R 9a ' , (CHR' ) r C(0)OH, (CHR' ) r C(0)R 9b , (CHR' ) r C (0) NR 9a R 9a ' , (CHR' ) r NR 9a C(0)R 9b , (CHR' ) r (0) C(0) NR 9a R 9a
  • R 9a and R 9a ' are selected from H,
  • R 9b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 9d is selected from methyl, CF 3 , C 2 _ 6 alkyl substituted with 0-3 R 9e , C 3 - 6 alkenyl, C 3 - 6 alkynyl, a C 3 - 10 carbocyclic residue substituted with 0-3 R 9c , and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-3 R 9c ;
  • R 9e is selected from C ⁇ _ 6 alkyl, C 2 _ 8 alkenyl, C2- 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OCi- 5 alkyl, OH, SH, (CH 2 ) r SC ⁇ _ 5 alkyl, (CH 2 ) r NR 9 f R 9 f , and (CH 2 ) r Phenyl;
  • R 9f at each occurrence, is selected from H, C 1 - 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 10 is selected from H, C 1 - 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, F, Cl, Br, I, N0 2 , CN, (CH 2 ) r OH, (CH 2 ) r OR 10d , (CH 2 ) r SR 10d , (CH 2 ) r NR 10a R 10a ', (CH 2 ) r C(0)OH, (CH 2 ) r C(O)R 10b , (CH 2 ) r C (O) NR 10a R 10a ' , (CH 2 ) r NR 10a C(O)R 10a , (CH 2 ) r NR 10a C (0) H,
  • R 10a and R 10a ' are selected from H, C ⁇ _ 6 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, a (CH 2 ) r -C 3 - 10 carbocyclic residue substituted with 0-5 R 10e , and a (CH 2 ) r _ 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 10e ;
  • R 10b at each occurrence, is selected from C 1 - 6 alkyl
  • R 10c is selected from C 1 - 6 alkyl, C 2 -8 alkenyl, C -s alkynyl, (CH 2 ) r C3-6 cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , N0 2 , CN, (CH 2 ) r NR 10f R 10f , (CH 2 ) r OH, (CH 2 ) r OCi_ 4 alkyl, (CH 2 ) r SC ⁇ _ 4 alkyl,
  • R 10d is selected from methyl, CF 3 , C 2 - 6 alkyl substituted with 0-3 R 10e , C 3 - 6 alkenyl, C 3 - 6 alkynyl, a C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 10c , and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-3 R 10c ;
  • R 10e at each occurrence, is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 -s alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl,
  • R 10f at each occurrence, is selected from H, C 1 - 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 10 when R 10 is -OH, R 9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
  • R lla and R lla ' are selected from H, C ⁇ -6 alkyl, C 3 _ 8 alkenyl, C 3 - 8 alkynyl, a (CH 2 ) r -C 3 - 10 carbocyclic residue substituted with 0-5 R lle , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R lle ;
  • R llb at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R llc is selected from C ⁇ _ 6 alkyl, C2-8 alkenyl, C2- 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , N0 2 , CN, (CH 2 ) r NR llf R llf , (CH 2 ) r OH, (CH 2 ) r OCi_ 4 alkyl, (CH 2 ) r SC ⁇ - 4 alkyl, (CH 2 ) r C(0)OH, (CH 2 ) r C(0)R llb , (CH 2 ) r C (0) NR llf R Hf , (CH 2 ) r NR llf C(0)R lla , (CH 2 ) r C (0) OC 1 - 4 alkyl, (CH 2 ) rOC (0) R llb , (CH 2 ) r C c
  • R lld is selected from methyl, CF 3 , C 2 -6 alkyl substituted with 0-3 R lle , C 3 - 6 alkenyl, C 3 - 6 alkynyl, and a C 3 - 10 carbocyclic residue substituted with 0-3 R llc ;
  • R lle is selected from C 1 - 6 alkyl, C2- 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 ) r SCi- 5 alkyl, (CH 2 ) r NR llf R llf , and (CH 2 ) r phenyl;
  • R llf at each occurrence, is selected from H, C 1 - 6 alkyl, and C 3 - 6 cycloalkyl;
  • R l2 i s selected from H, C ⁇ _ 6 alkyl, (CH 2 ) q OH, (CH 2 ) r C 3 - 6 cycloalkyl, and (CH 2 ) t Phenyl substituted with 0-3 R 12a ;
  • R 12a is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 ) r SCi_ 5 alkyl, (CH 2 ) r NR 9f R 9f , and (CH 2 ) r phenyl;
  • R 11 and R 12 join to form C 3 .- 7 cycloalkyl
  • R 1 a and R 14a ' are selected from H, C1-6 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 14c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R 1 ;
  • R 14b at each occurrence, is selected from Ci-g alkyl
  • R 1 c is selected from C ⁇ _ 6 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, (CH 2 ) w pheny1 ;
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, I, F, N0 2 , CN, (CHR') r NR 15a R 15a ⁇ (CHR') r OH, (CHR' ) r 0 (CHR' ) r R 15d , (CHR') r SH, (CHR') r C(0)H, (CHR' ) r S (CHR' ) r R 15d , (CHR' ) r C (O) OH, (CHR' ) r C (O) (CHR' ) r R 15b , (CHR') r C(0)NR 15a R 15a ', (CHR') r NR 15f C(0) (CHR') r R 15b , (CHR' ) r NR 15f C (0) NR 15a R 15a ' ,
  • R 15a and R 15a ' are selected from H, C ⁇ _ 6 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, a (CH 2 ) r -C 3 _ 10 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 15d is selected from C 3 _ 8 alkenyl, C 3 - 8 alkynyl, methyl, CF 3 , C 2 - 6 alkyl substituted with 0-3 R 15e , a (CH 2 ) r -C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 15e , and a (CH 2 ) r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R 15e.
  • R 15e is selected from C 1 - 6 alkyl, C - 8 alkenyl, C 2 -8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , alkyl, OH, SH, (CH 2 ) r SCi- 5 alkyl, (CH 2 ) r NR 15f R 15f , and (CH 2 ) r phenyl; R 15f , at each occurrence, is selected from H, C ⁇ - 6 alkyl, C 3 - 6 cycloalkyl, and phenyl;
  • R 16 is selected from C ⁇ _ 8 alkyl, C 2 _8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, I, F, N0 2 , CN, (CHR') r NR 16a R 16a ' , (CHR') r OH, (CHR') r O(CHR') r R 16d , (CHR') r SH, (CHR' ) r C (0) H, (CHR' ) r S (CHR' ) r R 16d , (CHR' ) r C (0) OH, (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0) NR 16a R 16 ' , (CHR' ) r NR 16f C (0) (CHR' ) r R 16b , (CHR
  • l6a anc ⁇ j ⁇ l ⁇ a' ⁇ ar each occurrence, are selected from H, C 1 - 6 alkyl, C 3 - 8 alkenyl, C 3 _ 8 alkynyl, a (CH ) r -C _ 10 carbocyclic residue substituted with 0-5 R 16e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R 16e ;
  • R 16b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 16d is selected from C 3 _ 8 alkenyl, C 3 - 8 alkynyl, methyl, CF 3 , C 2 - 6 alkyl substituted with 0-3 R 16e , a (CH2) r - 3 - ⁇ o carbocyclic residue substituted with 0-3 R 16e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R 16e ;
  • R 16e at each occurrence, is selected from C ⁇ _ 6 alkyl, C 2 -8 alkenyl, C 2 -8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl,
  • R 16f at each occurrence, is selected from H, C 1 - 5 alkyl, and C 3 - 6 cycloalkyl, and phenyl;
  • R 17 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 _ 8 alkynyl, (CHR') r OH, (CHR') r SH, (CHR' ) r OR 17d , (CHR' ) r SR 17d , (CHR' ) r NR 17a R 17a ', (CHR' ) r C (O) OH, (CHR' ) r C(0)R 17b , (CHR' ) r C (0) NR 17a R 17a ' , (CHR ' ) r NR 17a C (0) R 17b , (CHR' ) r NR 17 C (0) H, (CHR' ) r C(0)OR 17a , (CHR' ) r OC(0)R 17b , (CHR' ) r S (0) p R 17b , (CHR' ) r S(0) 2 NR 17a
  • R 17a and R 17a ' are selected from H, C ⁇ _ 6 alkyl, C 3 _ 8 alkenyl, C 3 - 8 alkynyl, a (CH 2 ) r -C 3 _ 10 carbocyclic residue substituted with 0-5 R 17e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 17e ;
  • R 17b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 17d is selected from methyl, CF 3 , C 1 - 6 alkyl substituted with 0-3 R 17e , C 3 _ 6 alkenyl, C 3 - 6 alkynyl, and a C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 17c ;
  • R 17e is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 )rSCi- 5 alkyl, (CH 2 ) r NR 17f R 17f , and (CH 2 ) r phenyl;
  • R 17f at each occurrence, is selected from H, C ⁇ - 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 18 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CHR') q OH, (CHR') q SH, (CHR' ) q OR 18d , (CHR' ) q SR 18d , (CHR' ) q NR 18a R 18a ', (CHR' ) r C (0) OH, (CHR' ) r C(0)R 18b , (CHR' ) r C (O) NR 18a R 18a ' , (CHR' ) g NR 18a C(0)R 18b , (CHR' ) q NR 18a C (O) H, (CHR' ) r C(0)OR 18a , (CHR' ) q OC(0)R 18b , (CHR' ) q S (O) p R 18b , (CHR' ) q S(0) 2 NR 18
  • R 18a and R 18a ' are selected from H, C1- 6 alkyl, C 3 - 8 alkenyl, C 3 _ 8 alkynyl, a (CH 2 ) r -C 3 - 10 carbocyclic residue substituted with 0-5 R 18e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 18e ;
  • R 18b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 18c at each occurrence, is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C2- 8 alkynyl, (CH 2 ) r C3-6 cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , N0 2 , CN, (CH 2 ) r NR 18f R 18f , (CH 2 ) r OH, (CH 2 )rOCi_ 4 alkyl, (CH 2 ) r SC ⁇ _ 4 alkyl,
  • R 18d is selected from methyl, CF 3 , C ⁇ _ 6 alkyl substituted with 0-3 R 18e , C 3 - 6 alkenyl, C 3 - 6 alkynyl, and a C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 18c ;
  • R 18e is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 )rSC ⁇ - 5 alkyl, (CH 2 ) r NR 18f R 18f , and (CH 2 ) r phenyl;
  • R 18f at each occurrence, is selected from H, C 1 - 6 alkyl, and C 3 - 6 cycloalkyl;
  • a is selected from 0 and 1;
  • e is selected from 0 and 1;
  • f is selected from 0 and 1, wherein e + f equals 1 or 2 ;
  • g is selected from 0, 1, 2 and 3;
  • h is selected from 0 and 1;
  • i is selected from 1, 2, 3, 4, and 5;
  • j is selected from 0, 1, 2, 3, 4, and 5;
  • k is selected from 0, 1, and 2 ;
  • 1 is selected from 0, 1, 2 and 3, wherein 1 + h equals 2 or 3 ;
  • v at each occurrence, is independently selected from 0, 1 , and 2 ;
  • t at each occurrence, is selected from 1 and 2;
  • w at each occurrence, is selected from 0 and 1;
  • r at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
  • s at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; q, at each occurrence, is selected from 1, 2, 3, 4, and 5 ; and
  • p at each occurrence, is selected from 1 and 2.
  • R 4 is absent or, taken with the nitrogen to which it is attached to form an N-oxide
  • R 7 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CHR') q 0H, (CHR') q OR 7d , (CHR' ) q NR 7a R 7a ' , (CHR') r C(0)R 7b , (CHR' ) r C(0)NR 7 R 7a ' , (CHR' ) q NR 7a C(0)R 7b , (CHR' ) q NR 7a C(0)H, (CHR' ) q S (0) 2 NR 7a R 7a ' , (CHR' ) q NR 7a S (0) 2 R 7b , (CHR' ) q NHC(0)NHR 7a , (CHR' ) g NHC (0) OR 7a , (CHR' ) q OC(0)NHR 7a , C ⁇ _ 6 haloalkyl, (C
  • R 9 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CHR') r OH, (CHR') r OR 9d , (CHR' ) r NR 9a R 9a ' , (CHR' ) r C(0)R 9b , (CHR' ) r C (O) NR 9a R 9 ' , (CHR') r NR 9a C(0)R 9b , (CHR' ) r NR 9a C(0)H, (CHR') r NR 9a C(0)NHR 9a , (CHR' ) r NR 9a S (O) 2 R 9b , C ⁇ _ 6 haloalkyl, a (CHR' ) r -C 3 _ ⁇ o carbocyclic residue substituted with 0-5 R 9c , and a (CHR') r -5-10 membered heterocyclic
  • R 10 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl ;
  • R 11 is selected from H, C 1 - 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q OR lld , (CH 2 ) q NR lla R lla ' , (CH 2 ) r C (0) R llb , (CH 2 ) r C (0) NR lla R lla ' , (CH 2 ) q NR lla C(0)R lla , (CH 2 ) q NR lla C(0)NHR lla , (CH 2 ) q NHC (0) NHR 7a , (CH 2 ) q NHC (O) OR 7a , (CH 2 ) q OC(0)NHR 7a , C ⁇ _ 6 haloalkyl, a (CH 2 ) r -C 3 _ ⁇ 0 carbocyclic residue substituted with 0-5 R lld
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR n R 12 ) ,
  • R 17 is selected from H
  • R 18 is selected from H
  • j is selected from 0, 1, and 2;
  • i is selected from 1 and 2 ;
  • s is selected from 0, 1, and 2;
  • g is selected from 0, 1, and 2.
  • R 1 is selected from H
  • R 2 is selected from H
  • the present invention provides novel compounds of formula (I) , wherein: E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR 1L R 12 ) .
  • R 7 is selected from H
  • R 8 is selected from H
  • R 12 is selected from H.
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C 2 _ 8 alkenyl, C 2 - 8 alkynyl, (CH ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 16 R 16a ⁇ (CHR') r OH, (CHR' ) r 0 (CHR' ) r R 16d , (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0)NR 16a R 16a ' ,
  • R 16a and R 16a ' are selected from H, methyl, ethyl, and a (CH 2 ) r -C 3 - 6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and 0CH 3 ;
  • R 16f at each occurrence, is selected from H; and r is selected from 0, 1, and 2.
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 and a (CR 3 'CR 3 ") r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, subtituted with 0-3 R 15 ;
  • R 3 ' and R 3 " at each occurrence, are selected from H;
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 15a R 15a ' , (CHR') r 0H, (CHR' ) r O (CHR' ) r R 15d , (CHR') r C(0) (CHR') r R 15b , (CHR' ) r C (0) NR 15 R 15a ' , (CHR') r NR 15f C(0) (CHR') r R 15b , (CHR') r NR 15f C(0)NR 15a R 15a ⁇ (CHR' ) r C (0) 0 (CHR' ) r R 15d , (CHR') r OC(0) (CHR') r R 15b , (CHR' ) r S (O) p (CHR' )
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl
  • R 15a and R 15a ' are selected from H, C ⁇ - 6 alkyl, a (CH ) r -C 3 _ 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from C ⁇ _ 6 alkyl, a (CH 2 ) r -C 3 - 6 carbocyclic residue substituted with 0-3 R 15e , and (CH ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C ⁇ _ 6 alkyl, Cl, F, Br, CN, (CF 2 ) r CF 3 , and OH.
  • ring D is selected from a C 3 - 6 carbocyclic residue
  • R 7 is selected from H
  • R 8 is selected from H.
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, ( (CCHH 22 )) rr CC 33 -- 6 6 ccyyccllooaallkkyyll,, CCll,, BBrr,, FF,,CCNN,, (CHR') r NR 16a R 16a ⁇ (CHR') r OH, (CHR' ) r O (CHR' ) r R 16d , (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0) NR 16a R 16a ' , (CHR') r NR 16f C(0) (CHR') r R 16b , (CHR' ) r S (O) p (CHR' ) r R 16b , (CHR' )
  • R i6a anc : i6a' t a ⁇ each occurrence, are selected from H, methyl, ethyl, and a (CH2) r -C3-6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H; and r is selected from 0, 1, and 2.
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 and a (CR 3 'CR 3 " ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, subtituted with 0-3 R 15 ;
  • R 3 ' and R 3 " at each occurrence, are selected from H;
  • R 15 at each occurrence, is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN,
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl
  • R 15a and R 15a ' are selected from H, Ci- 6 alkyl, a (CH 2 ) r - 3 - 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from C ⁇ _ 6 alkyl, a (CH 2 ) r -C 3 - 6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C ⁇ _ 6 alkyl, Cl, F, Br, I, CN, (CF 2 ) r CF 3 , and OH.
  • G is selected from ⁇ .
  • R 1 is selected from H
  • both X 1 and X 2 cannot be C;
  • Z 2 is selected from NR 1 ', 0, and S. [17]
  • the present invention provides novel compounds of formula (I) , wherein:
  • R 17 is selected from H
  • R 18 is selected from H
  • j is selected from 0, 1, and 2;
  • i is selected from 1 and 2;
  • s is selected from 0, 1, and 2;
  • g is selected from 0, 1, and 2.
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR n R 12 ) .
  • R 7 is selected from H
  • R 8 is selected from H
  • R 12 is selected from H.
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F,CN, (CHR') r NR 16a R 16a ', (CHR') r OH, (CHR' ) r O (CHR' ) r R 16d , (CHR' ) r C (0) (CHR' ) r R 16b , (CHR' ) r C (0) NR 16a R 16a ' , (CHR') r NR 16f C(0) (CHR') r R 16b , (CHR' ) r S (0) p (CHR' ) r R 16b , (CHR' ) r S (0) 2 NR 16a R 16a ' , (CHR' )
  • R 16a and R 16a ' are selected from H, methyl, ethyl, and a (CH 2 ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H;
  • r is selected from 0, 1, and 2.
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 -6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 15 R 15a ⁇ (CHR') r OH, (CHR' ) r O (CHR' ) r R 15d , (CHR') r C(0) (CHR') r R 15b , (CHR' ) r C (O) NR 15a R 15a ' , (CHR' ) r NR 15f C (0) (CHR' ) r R 15b ,
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl ;
  • R 15a and R 15a ' are selected from H, C ⁇ _ 6 alkyl, a (CH 2 ) r ⁇ C 3 _ 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from C ⁇ _ 6 alkyl, a (CH 2 ) r _ C 3 - 6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r _ 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C ⁇ _ 6 alkyl, Cl, F, Br, I, CN, (CF 2 ) r CF 3 , and OH.
  • the present invention provides novel compounds of formula (I) , wherein:
  • ring D is selected from a C 3 _ 6 carbocyclic residue
  • R 7 is selected from H
  • R 8 is selected from H.
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F,CN,
  • R 16a and R 16a ' are selected from H, methyl, ethyl, and a (CH 2 ) r ⁇ C 3 - 6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H;
  • r is selected from 0, 1, and 2.
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 15a R 15a ⁇ (CHR') r OH, (CHR' ) r O (CHR' ) r R 15d , (CHR') r C(0) (CHR') r R 15b , (CHR' ) r C (0) NR 15a R 15a ' , (CHR' ) r NR 15f C (0) (CHR' ) r R 15b ,
  • R 15a and R 15a ' are selected from H, Ci- 6 alkyl, a (CH 2 ) r ⁇ 3 _ 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from Ci- 6 alkyl, a (CH 2 ) r ⁇ C 3 - 6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r _ 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C ⁇ _ 6 alkyl, Cl, F, Br, CN, (CF 2 ) r CF 3 , and OH.
  • the present invention provides novel compounds of formula (I) , wherein the compound of formula I is selected from:
  • (+/-) -N-3- [cis-6-fluoro-2 , 3 , 3a, 4, 9 , 9a-hexahydro-lH- benz [f] isoindol-2-yl] -n-prop-1-yl-N' -3- acetylphenylurea;
  • the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
  • the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention.
  • the present invention provides a method for treating or preventing inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention.
  • the present invention provides a method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of the compounds of the present invention.
  • the present invention provides a method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of compounds of the present invention.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) :
  • ring A is selected from
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR n R 12 )
  • ring D is selected from a C 3 - 6 carbocyclic residue and a 5 or 6 membered heterocycle
  • G is selected from -C(0)R 3 , -C(0)NR 2 R 3 , -C(0)OR 3 , -
  • W at each occurrence, is independently selected from C or N, provided at least two of W are C;
  • X 1 and X 2 are independently selected from C and N;
  • Z 1 is selected from C and N;
  • Z 2 is selected from NR 1 ', 0, S and C;
  • R 1 , R 1 ' and R 2 are independently selected from H, C ⁇ - 8 alkyl, C 3 -s alkenyl, C 3 - 8 alkynyl, (CH 2 ) r C3-6 cycloalkyl, and a (CH 2 ) r _ 3 _ ⁇ o carbocyclic residue substituted with 0-5 R a ;
  • R la is independently selected from H, C ⁇ _ 6 alkyl, -OH, - CN, -N0 2 , (CH 2 ) r C3-6 cycloalkyl, and a (CH 2 ) r -C 3 - ⁇ o carbocyclic residue substituted with 0-5 R a ;
  • R b at each occurrence, is selected from H, Ci- 6 alkyl, C 3 - 6 cycloalkyl, and phenyl;
  • R c at each occurrence, is selected from Ci- 6 alkyl, C 3 - 6 cycloalkyl, and phenyl;
  • R 1 and R 2 join to form a 5, 6, or 7- membered ring substituted with 0-3 R a ;
  • R 3 is selected from a (CR 3 'R 3 ") r -C 3 - ⁇ o carbocyclic residue substituted with 0-5 R 15 and a (CR 3 'R 3 ") r -5- 10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 15 ;
  • R 3 ' and R 3 " are selected from H, Cl-6 alkyl, (CH 2 ) r 3 - 6 cycloalkyl, and phenyl;
  • R 4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C ⁇ _ 8 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, (CH 2 ) q C (0) R b , (CH 2 ) q C (0)NR a R 4a ' , (CH 2 ) q C(0)OR 4 , and a (CH ) r -C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 4c ;
  • R a and R a ' are selected from H, Ci- 6 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, and phenyl;
  • R 4b at each occurrence, is selected from C ⁇ _ 6 alkyl, C _ 8 alkenyl, (CH 2 ) r C 3 - 6 cycloalkyl, C2- 8 alkynyl, and phenyl ;
  • R c at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 7 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR 7d , (CH 2 ) q SR 7d ,
  • R 7a and R 7a ' are selected from H,
  • R 7b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 7d is selected from methyl, CF 3 , C ⁇ _ 6 alkyl substituted with 0-3 R 7e , C 3 - 6 alkenyl, C 3 - 6 alkynyl, and a C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 7c ;
  • R 7e is selected from Ci- 6 alkyl, C2- 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r 0C ⁇ _ 5 alkyl, OH, SH, (CH 2 ) r SCi_ 5 alkyl, (CH 2 ) r NR 7 f R 7 f , and (CH 2 ) r phenyl;
  • R 7f is selected from H, Ci- 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 8 is selected from H, C ⁇ _ 6 alkyl, C 3 - 6 cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 8a ;
  • R 8a at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 8b is selected from H, Ci- 6 alkyl, C 3 - 6 cycloalkyl, OH, CN, and (CH 2 ) r -phenyl ;
  • R 9 is selected from H, C ⁇ _ 6 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, F, Cl, Br, I, N0 , CN, (CH 2 ) r OH, (CH 2 ) r SH, (CH 2 ) r OR 9d , (CH 2 ) r SR 9d , (CH 2 ) r NR 9a R 9a ', (CH 2 ) r C (0) OH, (CH 2 ) r C(0)R 9b , (CH 2 ) r C(0)NR 9a R 9a ', (CH 2 ) r NR 9a C (O) R 9a , (CH 2 ) r NR 9a C (0) H, (CH 2 ) r NR 9a
  • R 9a and R 9a ' are selected from H,
  • R 9b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 9d is selected from methyl, CF 3 , Ci- 6 alkyl substituted with 0-3 R 9e , C 3 - 6 alkenyl, C 3 - 6 alkynyl, a C 3 - 10 carbocyclic residue substituted with 0-3 R 9c , and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-3 R 9c ;
  • R 9e is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r C3- 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OCi- 5 alkyl, OH, SH, (CH 2 ) r SC ⁇ - 5 alkyl, (CH 2 ) r NR 9f R 9f , and (CH 2 ) r phenyl;
  • R 9f at each occurrence, is selected from H, C - 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 10 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 _ 8 alkynyl, F, Cl, Br, I, N0 2 , CN, (CH 2 ) r 0H, (CH 2 ) r OR 10d , (CH 2 ) r SR 10d , (CH 2 ) r NR 10 R 10a ' , (CH 2 ) r C(0)0H, (CH 2 ) r C(O)R 10b , (CH 2 ) r C (O) NR 10a R 10a ' , (CH 2 ) r NR 10a C(O)R 10a , (CH 2 ) r NR 10a C(O)H, (CH 2 ) r C(O)OR 10a , (CH 2 ) r OC(O)R 10b , (CH 2 ) r S (0) p R 10b , (CH 2 ) r S(O)
  • R 10a and R 10a ' are selected from H, Ci-6 alkyl, C 3 - 8 alkenyl, C 3- . 8 alkynyl, a (CH 2 ) r -C 3 - 10 carbocyclic residue substituted with 0-5 R 10e , and a (CH 2 ) r ⁇ 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R 10e ;
  • R 10b is selected from Ci- 6 alkyl, C2-8 alkenyl, C2- 8 alkynyl, a (CH 2 ) r _ C 3 - 6 carbocyclic residue substituted with 0-2 R 10e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 10e ;
  • R 10e at each occurrence, is selected from Ci- 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl,
  • R 10f at each occurrence, is selected from H, C ⁇ _ 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 10 when R 10 is -OH, R 9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
  • R 11 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR lld , (CH 2 ) q SR lld , (CH 2 ) q NR lla R lla ', (CH 2 ) r C (0) OH, (CH 2 ) r C(0)R llb , (CH 2 ) r C(0)NR lla R lla ', (CH 2 ) q NR lla C (0) R llb , (CH 2 ) q NR lla C (0) R llb , (CH 2 ) q NR lla C (0) NR lla R lla , (CH 2 ) r C(0)0R lla , (CH 2 ) q OC(0)R llb , (CH 2 )
  • R lla and R lla ' are selected from H, C ⁇ _ 6 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, a (CH 2 ) r -C 3 - 10 carbocyclic residue substituted with 0-5 R lle , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R lle ;
  • R llb at each occurrence, is selected from Ci- 6 alkyl
  • R llc is selected from C _ 6 alkyl, C 2 _ 8 alkenyl, C _ 8 alkynyl, (CH 2 ) r C 3 _ 6 cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , N0 2 , CN, (CH 2 ) r NR llf R llf , (CH 2 ) r 0H, (CH 2 ) r OC ⁇ _ 4 alkyl, (CH 2 ) r SCi- 4 alkyl, (CH 2 ) r C(0)OH, (CH 2 ) r C(0)R llb , (CH 2 ) r C (O) NR llf R Hf , (CH 2 ) r NR llf C(0)R lla , (CH 2 ) r C (O) OC 1 - 4 alkyl, (CH 2 ) r 0C(0)R llb , (CH 2 ) r
  • R lld is selected from methyl, CF 3 , C ⁇ _ 6 alkyl substituted with 0-3 R lle , C 3 _ 6 alkenyl, C 3 - 6 alkynyl, and a C 3 - 10 carbocyclic residue substituted with 0-3 R llc ;
  • R lle is selected from Ci- 6 alkyl, C 2 - 8 alkenyl, C 2 _ 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 ) r SCi- 5 alkyl, (CH 2 ) r NR llf R llf , and (CH 2 ) r phenyl;
  • R llf at each occurrence, is selected from H, Ci- 6 alkyl, and C 3 _ 6 cycloalkyl;
  • R 12 is selected from H, C ⁇ _ 6 alkyl, (CH 2 ) q OH, (CH 2 ) r C 3 - 6 cycloalkyl, and (CH 2 ) t P nen yl substituted with 0-3 R 12a ;
  • R 12a is selected from Ci- 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 -- 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 )rSC ⁇ - 5 alkyl, (CH 2 ) r NR 9f R 9f , and (CH 2 ) r phenyl;
  • R 11 and R 12 join to form C 3 _ 7 cycloalkyl
  • R 1 a and R 14a ' are selected from H, C ⁇ _ 6 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, and (CH 2 ) r phenyl substituted with 0-3 R 14c , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R 14c ;
  • R 14b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 1 c is selected from C ⁇ _ 6 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OCi_ 5 alkyl, OH, (CH 2 ) w phenyl;
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, I, F, N0 , CN, (CHR') r NR 15 R 15a ' , (CHR') r OH, (CHR' ) r O (CHR' ) r R 15d , (CHR') r SH, (CHR') r C(0)H, (CHR' ) r S (CHR' ) r R 15d , (CHR' ) r C (0) OH, (CHR' ) r C (O) (CHR' ) r R 15b , (CHR') r C(0)NR 15a R 15a ', (CHR') r NR 15f C(0) (CHR') r R 15b , (CHR' ) r NR 15f C (0) NR 15a R 15a ' , (CHR' ) r
  • R 15a and R 15a ' are selected from H, C ⁇ _ 6 alkyl, C 3 _ 8 alkenyl, C 3 _ 8 alkynyl, a (CH 2 ) r -C 3 _ 10 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r _ 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from Ci- 6 alkyl
  • R 15d is selected from C 3 -. 8 alkenyl, C 3 - 8 alkynyl, methyl, CF 3 , C ⁇ _ 6 alkyl substituted with 0-3 R 15e , a (CH 2 ) r -C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 15e , and a (CH 2 ) r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 Rl5e.
  • R i5e at each occurrence, is selected from C ⁇ _ 6 alkyl, C 2 -8 alkenyl, C 2 -s alkynyl, (CH ) r C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 ) r SCi_ 5 alkyl, (CH 2 ) r NR i5f R 15f , and (CH 2 ) r phenyl; R l5f , at each occurrence, is selected from H, Ci- 6 alkyl, C 3 - 6 cycloalkyl, and phenyl;
  • R 16 is selected from C ⁇ _ 8 alkyl, C 2 -8 alkenyl, C 2 -8 alkynyl, (CH 2 ) r C3-6 cycloalkyl, Cl, Br, I, F, N0 2 , CN, (CHR' ) r NR l6a R l6a ' , (CHR') r OH, (CHR') r O(CHR') r R l6d , (CHR') r SH, (CHR' ) r C (O) H, (CHR' ) r S (CHR' ) r R l6d , (CHR' ) r C (O) OH, (CHR') r C(0) (CHR') r R l6b , (CHR' ) r C (0) NR 16a R 16a ' ,
  • R 16a and R 16a ' are selected from H, Ci- 6 alkyl, C 3 _ 8 alkenyl, C 3 - 8 alkynyl, a (CH 2 ) r -C 3 _ 10 carbocyclic residue substituted with 0-5 R 16e , and a (CH 2 ) r ⁇ 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R 16e ;
  • R 16b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 16e at each occurrence, is selected from C ⁇ _ 6 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) r C 3 _ 6 cycloalkyl,
  • R 16f at each occurrence, is selected from H, C 1 - 5 alkyl, and C 3 - 6 cycloalkyl, and phenyl;
  • R 17 is selected from H, C ⁇ _ 6 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR 17d , (CH 2 ) q SR 17d , (CH 2 ) q NR 17a R 17a ', (CH 2 ) r C (0) OH, (CH 2 ) r C (0) R 17b , (CH 2 ) r C (O) NR 17a R 17a ' , (CH 2 ) q NR 17a C(0)R 17b , (CH 2 ) q NR 17a C(0)H, (CH 2 ) r C(0)OR 17a , (CH 2 ) q OC(0)R 17b , (CH 2 ) q S (O) p R 17b , (CH 2 ) q S(0) 2 NR l7 R 17a ', (CH 2 )
  • R 17a and R 17a ' are selected from H, C ⁇ _ 6 alkyl, C 3 - 8 alkenyl, C 3 _ 8 alkynyl, a (CH 2 ) r -C 3 _ 10 carbocyclic residue substituted with 0-5 R 17e , and a (CH 2 ) r ⁇ 5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 17e ;
  • R 17b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 17d is selected from C ⁇ _ 6 alkyl substituted with 0-3 R 17e , C 3 _ 6 alkenyl, C 3 - 6 alkynyl, and a C 3 _ ⁇ o carbocyclic residue substituted with 0-3 R 17c ;
  • R 17e is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OCi- 5 alkyl, OH, SH, (CH 2 ) r SCi_ 5 alkyl, (CH 2 ) r NR 17f R 17f , and (CH 2 ) r phenyl;
  • R 17f is selected from H, Ci- 6 alkyl, and C 3 - 6 cycloalkyl;
  • R 18 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q SH, (CH 2 ) q OR 18d , (CH 2 ) q SR 18d , (CH 2 ) q NR l8a R 18a ', (CH 2 ) r C (O) OH, (CH 2 ) r C(0)R 18b , (CH 2 ) r C(0)NR 18a R 18a ', (CH 2 ) q NR 18a C (O) R 18b , (CH 2 ) q NR 18a C (O) H, (CH 2 ) r C(0)OR 18a , (CH 2 ) q OC(0)R 18b , (CH 2 ) q S (0) p R 18b , (CH 2 ) q S(0) 2 NR 18a R 18a ⁇ (CH 2 ) )
  • R 18a and R 18a ' are selected from H, Ci- 6 alkyl, C 3 _ 8 alkenyl, C 3 - 8 alkynyl, a (CH 2 ) r -C 3 _ 10 carbocyclic residue substituted with 0-5 R 18e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-3 R 18e ;
  • R 18b at each occurrence, is selected from C ⁇ _ 6 alkyl
  • R 18c at each occurrence, is selected from C ⁇ _ 6 alkyl, C _ 8 alkenyl, C2-8 alkynyl, (CH 2 ) r C 3 -6 cycloalkyl, Cl, Br, I, F, (CF 2 ) r CF 3 , N0 2 , CN, (CH 2 ) r NR 18f R 18f , (CH 2 ) r OH, (CH 2 )rOC ⁇ - 4 alkyl, (CH 2 ) r SC ⁇ _ 4 alkyl,
  • R 18d is selected from methyl, CF 3 , Ci- 6 alkyl substituted with 0-3 R 18e , C 3 _ 6 alkenyl, C 3 _ 6 alkynyl, and a C 3 - 10 carbocyclic residue substituted with 0-3 R 18c ;
  • R 18e is selected from C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 6 cycloalkyl, Cl, F, Br, I, CN, N0 2 , (CF 2 ) r CF 3 , (CH 2 ) r OC ⁇ _ 5 alkyl, OH, SH, (CH 2 ) r SC ⁇ - 5 alkyl, (CH 2 ) r NR 18f R 18f , and (CH 2 ) r phenyl;
  • R 18f is selected from H, Ci- 6 alkyl, and C 3 - 6 cycloalkyl;
  • a is selected from 0 and 1;
  • e is selected from 0 and 1;
  • f is selected from 0 and 1, wherein e + f equals 1 or 2;
  • g is selected from 0, 1, 2 and 3;
  • h is selected from 0 and 1;
  • i is selected from 0, 1, 2, 3, 4, and 5;
  • j is selected from 0, 1, 2, 3, 4, and 5;
  • k is selected from 0, 1, and 2;
  • 1 is selected from 0, 1, 2 and 3, wherein 1 + h equals 2 or 3 ;
  • v at each occurrence, is independently selected from 0,
  • t is selected from 1 and 2;
  • w is selected from 0 and 1;
  • r is selected from 0, 1, 2, 3, 4, and 5;
  • s is selected from 0, 1, 2, 3, 4, and 5;
  • q is selected from 1, 2, 3, 4, and 5;
  • the present invention provides method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 4 is absent or, taken with the nitrogen to which it is attached to form an N-oxide
  • R 7 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q OR 7d , (CH 2 ) q NR 7a R 7 ' , (CH 2 ) r C(0)R 7b , (CH 2 ) r C(0)NR 7a R 7a ', (CH 2 ) q NR 7a C(0) R 7a , (CH 2 ) q NR 7a C(0)H, (CH 2 ) q S(0) 2 NR 7a R 7a ', (CH 2 ) q NR 7a S(0) 2 R 7b .
  • R 9 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r 0H, (CH 2 ) r OR 9d , (CH 2 ) r NR 9a R 9a ' , (CH 2 ) r C(0)R 9b , (CH 2 ) r C(0)NR 9a R 9a ', (CH 2 ) r NR 9a C (O) R 9b , (CH 2 ) r NR 9a C(0)H, (CH 2 ) r NR 9a C (0) NHR 9a ,
  • R 10 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl ;
  • R 11 is selected from H, C ⁇ _ 6 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) q OH, (CH 2 ) q OR lld , (CH 2 ) q NR lla R lla ' , (CH 2 ) r C(0)R llb , (CH 2 ) r C(0)NR lla R lla ',
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR R 12 ) ,
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • R 17 is selected from H
  • R 18 is selected from H
  • j is selected from 0, 1, and 2 ;
  • i is selected from 1 and 2 ;
  • s is selected from 0, 1, and 2;
  • g is selected from 0, 1, and 2.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein: R 1 is selected from H;
  • R 2 is selected from H
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR 1:L R 12 ) .
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 7 is selected from H
  • R 8 is selected from H
  • R 12 is selected from H.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C _ 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 16a R 16a ', (CHR') r OH, (CHR' ) r O (CHR' ) r R 16d , (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0) NR 16a R 16a ' , (CHR') r NR 16f C(0) (CHR') r R 16b , (CHR' ) r S (0) p (CHR' ) r R 16b , (CHR' ) r S (0) 2 NR 16a R 16a ' , (CHR' ) r
  • R l6a anc j R l6a' f a t each occurrence, are selected from H, methyl, ethyl, and a (CH ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H;
  • r is selected from 0, 1, and 2.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 ;
  • R 3 ' and R 3 " at each occurrence, are selected from H;
  • R 15 at each occurrence, is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN,
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl ;
  • R 15a and R 15a ' are selected from H, C ⁇ _ 6 alkyl, a (CH2) r _ C 3 - 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from C ⁇ _ 6 alkyl, a (CH 2 )r _ C 3 _ 6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r _ 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C ⁇ _ 6 alkyl, Cl, F, Br, I, CN, (CF 2 ) r CF 3 , and OH.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • ring D is selected from a C 3 - 6 carbocyclic residue
  • R 7 is selected from H
  • R 8 is selected from H.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C 2 - 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, I, F, CN, (CHR') r NR 16a R 16a ', (CHR') r OH, (CHR' ) r O (CHR' ) r R 16d , (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0) NR 16a R 16a ' , (CHR') r NR 16f C(0) (CHR') r R 16b , (CHR' ) r S (0) p (CHR' ) r R 16b , (CHR' ) r S (O) 2 NR 16a R 16a ' , (CHR' , (CHR'
  • R 16a and R 16a ' are selected from H, methyl, ethyl, and a (CH ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H;
  • r is selected from 0, 1, and 2.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 ;
  • R 3 ' and R 3 " at each occurrence, are selected from H;
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 15a R 15a ⁇ (CHR') r 0H, (CHR' ) r O (CHR' ) r R 15d , (CHR') r C(0) (CHR') r R 15b , (CHR' ) r C (0) NR 15a R 15a ' , (CHR') r NR 15f C(0) (CHR') r R 15b , (CHR' ) r NR 15f C (O) NR 15a R 15a ' , (CHR' ) r C (0) O (CHR' ) r R 15d .
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl ;
  • R 15a and R 15a ' are selected from H, C ⁇ _ 6 alkyl, a (CH 2 ) r -C 3 _ 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from Ci- 6 alkyl, a (CH 2 ) r -C 3 _ 6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C _ 6 alkyl, Cl, F, Br, I, CN, (CF 2 ) r CF 3 , and OH.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein: G is selected from , and
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 1 is selected from H
  • both X 1 and X 2 cannot be C;
  • Z 2 is selected from NR 1 ', O, and S.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • R 17 is selected from H
  • R 18 is selected from H
  • j is selected from 0, 1, and 2;
  • i is selected from 1 and 2;
  • s is selected from 0, 1, and 2;
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR 1:L R 12 ) .
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 7 is selected from H
  • R 8 is selected from H
  • R 12 is selected from H.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, I, F, CN, (CHR') r NR 16a R 16a ', (CHR') r OH, (CHR' ) r O (CHR' ) r R 16d , (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0) NR 16a R 16a ' , (CHR') r NR 16f C(0) (CHR') r R 16b , (CHR' ) r S (0) p (CHR' ) r R 16b , (CHR') r S(0) 2 NR 16a R 16a ', (CHR' ) r
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H;
  • r is selected from 0, 1, and 2.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 ;
  • R 3 ' and R 3 " at each occurrence, are selected from H;
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 15a R 15a ⁇ (CHR') r OH, (CHR' ) r O (CHR' ) r R 15d , (CHR') r C(0) (CHR') r R 15b , (CHR' ) r C (0) NR 15a R 15a ' , (CHR' ) r NR 15f C (0) (CHR' ) r R 15b ,
  • R' C 2 - 8 alkynyl substituted with 0-3 R' , (CHR') r phenyl substituted with 0-3 R 15e , and a (CH 2 ) r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl ;
  • R 15a and R 15a ' are selected from H, Ci- 6 alkyl, a (CH 2 ) r -C 3 _ 6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from C ⁇ _ 6 alkyl, a (CH 2 ) r -C 3 _ 6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, O, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from C ⁇ _ 6 alkyl, Cl, F, Br, I, CN, (CF 2 ) r CF 3 , and OH.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • ring D is selected from a C3_6 carbocyclic residue
  • R 7 is selected from H
  • R 8 is selected from H.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein:
  • R 16 is selected from methyl, ethyl, propyl, iso-propyl, C _ 8 alkenyl, C 2 _ 8 alkynyl, (CH 2 ) r C3-6 cycloalkyl, Cl, Br, I, F, CN, (CHR') r NR 16a R 16a ', (CHR') r OH, (CHR' ) r 0 (CHR' ) r R 16d , (CHR') r C(0) (CHR') r R 16b , (CHR' ) r C (0) NR 16a R 16a ' , (CHR') r NR 16f C(0) (CHR') r R 16b , (CHR' ) r S (0) p (CHR' ) r R 16b , (CHR' ) r S (0) 2 NR 16a R 16a ' , (CHR' ) r
  • R l6a and R 16a ' are selected from H, methyl, ethyl, and a (CH 2 ) r ⁇ C 3 _ 6 carbocyclic residue substituted with 0-2 R 16e ;
  • R 16e at each occurrence, is selected from methyl, ethyl, Cl, F, Br, I, CN, CF 3 , and OCH 3 ;
  • R 16f at each occurrence, is selected from H;
  • r is selected from 0, 1, and 2.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I), wherein:
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 ;
  • R 3 ' and R 3 " at each occurrence, are selected from H;
  • R 15 is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br, F, CN, (CHR') r NR 15a R 15a ', (CHR') r OH, (CHR' ) r O (CHR' ) r R 15d , (CHR') r C(0) (CHR') r R 15b , (CHR' ) r C (O) NR 15a R 15 ' , (CHR' ) r NR 15f C (0) (CHR' ) r R 15b ,
  • R' at each occurrence, is selected from H, and C ⁇ _ 6 alkyl
  • R 15a and R 15a ' are selected from H, C _6 alkyl, a (CH2) r _ C 3 -6 carbocyclic residue substituted with 0-5 R 15e , and a (CH 2 ) r -5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ;
  • R 15b is selected from Ci- 6 alkyl, a (CH2)r ⁇ C3_6 carbocyclic residue substituted with 0-3 R 15e , and (CH 2 ) r ⁇ 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from N, 0, and S, substituted with 0-2 R 15e ; and
  • R 15e is selected from Ci- 6 alkyl, Cl, F, Br, I, CN, (CF 2 )rCF 3 , and OH.
  • the present invention provides a method of modulating chemokine receptor by administering a compound of formula (I) , wherein the compound is selected from: N-3- [cis-2, 3 , 3a, 4, 9, 9a-hexahydro-lH-benz [f] isoindol-2- yl] -n-prop-1-yl-N' -3-acetylphenylurea;
  • E is selected from
  • E is selected from
  • E is selected from
  • E is selected from
  • E is selected from -(CR 7 R 8 ) (CR 9 R 10 ) V -(CR 11 R 12 ) . In another embodiment, E is selected from
  • E is selected from
  • R 8 , R 10 , and R 12 are H.
  • R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are H.
  • ring D is selected from a C 3 _ 6 carbocyclic residue.
  • ring D is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl .
  • ring D is cyclohexyl
  • G is selected from C(0)NR 2 R 3 .
  • G is selected from
  • R 1 , R 1 ' , and R 2 are equal to
  • R 3 is selected from a (CR 3 'R 3 " ) r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 and a (CR 3 'CR 3 ") r -5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, subtituted with 0-3 R 15 .
  • R 3 is selected from a (CR 3 'R 3 ") r -C 3 _ 6 carbocyclic residue substituted with 0-2 R 15 .
  • R 3 is phenyl substitued with 0-2 R 15 .
  • R 4 is absent.
  • R 15 at each occurrence, is selected from C ⁇ _ 8 alkyl, (CH 2 ) r C 3 - 6 cycloalkyl, Cl, Br,
  • A is selected from
  • E is selected from - (CR 7 R 8 ) - (CR 9 R 10 ) v - (CR n R 12 ) , and
  • ring D is cyclohexyl
  • G is -C(0)NR 2 R 3 ;
  • R 1 ad R 2 are H
  • R 3 is phenyl substituted with 0-3 R 15 ;
  • R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are H; R 15 is selected from F and acetyl;
  • R 16 is F
  • g 0;
  • s 1;
  • a is 0 or 1
  • d is 0 or 1
  • c is 0 or 1;
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds .
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • any variable e.g., R a
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R a e.g., R a
  • said group may optionally be substituted with up to two R a groups and R a at each occurrence is selected independently from the definition of R a .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
  • C ⁇ _ 8 alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • C ⁇ _ ⁇ o alkyl is intended to include Ci, C 2 , C 3 , C 4 , C 5 , C ⁇ , C 7 , Cs, C 9 , and C 10 alkyl groups.
  • Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
  • C 2 - 10 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , CQ , C 7 , Cs, C 9 , and C 10 alkenyl groups.
  • Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • C ⁇ _ 10 alkoxy is intended to include Ci, C 2 , C 3 , C 4 , C 5 , C , C ⁇ , C 8 / Cg , and C 10 alkoxy groups.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • Alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like.
  • C 2 - 10 alkynyl is intended to include C 2 , C 3 , C , C 5 , C 6 , C 7 , C 8 , C 9 , and C ⁇ 0 alkynyl groups.
  • C 3 - 6 cycloalkyl is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C 7 cycloalkyl.
  • C 3 _ 7 cycloalkyl is intended to include C 3 , C 4 , C 5 , C ⁇ , , and C 7 cycloalkyl groups.
  • the compounds of Formula I can also be quaternized by standard techniques such as alkylation of the cyclic amines with an alkyl halide to yield quaternary piperidinium salt products of Formula I.
  • Such quaternary piperidinium salts would include a counterion.
  • counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • the term "5-6-membered cyclic ketal” is intended to mean 2 , 2-disubstituted 1,3- dioxolane or 2 , 2-disubstituted 1,3 -dioxane and their derivatives .
  • Carbocycle or “carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7 , 8, 9, 10, 11, 12, or 13 -membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0]bicyclodecane (decalin) , [2.2.2 ] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
  • heterocycle or “heterocyclic system” is intended to mean a stable 4, 5, 6, or 7-membered monocyclic or bicyclic or 7 , 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 , or 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
  • aromatic heterocyclic system is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7 , 8, 9, or 10- membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, O and S.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2- dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1, 2 , 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl , benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aff-carbazolyl, ⁇ -carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl
  • Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl, 1, 2 , 4-triazolyl, 1,2,3- triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non- toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc ... ) the compounds of the present invention may be delivered in prodrug form.
  • the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
  • Prodrugs are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
  • terapéuticaally effective amount of a compound of this invention means an amount effective to modulate chemokine receptor activity or treat the symptoms of asthma or an allergic disorder in a host.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated in their entirety by reference.
  • novel compounds of Formula I may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • all proposed reaction conditions including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art.
  • One skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of Formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described.
  • Oxidation Compounds of Formula I may be prepared by procedures depicted in Scheme 1 from compounds of Formula I in which R4 is absent. It is understood that the chemistry is shown for only one A group of Formula I and that similar transformations may be preformed on other A groups.
  • the quaternary salts of Formula I can be synthesized by alkylation with an alkylhalide such as methyl iodide, benzyl bromide, bromoacetate, etc. in a suitable solvent such as THF, DMF, DMSO, etc. at room temperature to reflux temperature of the solvent.
  • the N- oxides of Formula I can be made by the general protocols of Deady, Syn . Comm. 1977, 7.. 509 and references therein, with minor modification depending on the substitution of Formula I which should be readily recognized by one skilled in the art.
  • the N-oxides are created by oxidation with mCPBA in an inert solvent such as methylene chloride .
  • R 5 shown in the schemes and in Table 1 are representative of the phenyl ring which is a part of ring A in the claims.
  • Formula II may be reacted with Formula IV, wherein X is a good leaving group such as but not limited to Cl, Br, or imidazole, in the presence of a base such as, but not limited to, triethylamine or pyridine to provide compounds of
  • Formula II may be reacted with Formulas VI, VII, or VIII wherein X is a good leaving group such as but not limited to ethoxide, phenoxide, or methylsulfide to provide compounds of Formula I according to procedures described in Hoffman, et.al. J. Med. Chem. 1983, 26, 140 and references therein.
  • Scheme 3
  • compounds of Formula I can be synthesized by coupling compounds of Formula II with halogenated heterocycles of Formula IX, where lA and Z ⁇ are defined in the scope, as described in Scheme 3. It is understood that the chemistry is shown for only one A group of Formula I and heterocycle and that similar transformations may be preformed on other A groups or halogenated heterocycles. This procedure essentially follows the general procedures of Hong, Y. et. al . , Tet . Lett . 1997, 3_8, 5607 and references therein, with minor modification depending on the Formula IX which should be readily recognized by one skilled in the art.
  • the reaction can be preformed in an inert solvent such as, but not limited to, toluene at room temperature to the reflux temperature of the solvent with a Pd-catalyst such as Pd2(dba)3 and a base such as sodium t-butoxide.
  • an inert solvent such as, but not limited to, toluene at room temperature to the reflux temperature of the solvent with a Pd-catalyst such as Pd2(dba)3 and a base such as sodium t-butoxide.
  • halogenated heterocycles that are not commercial available can be synthesized by methods known in the art and are exemplified by, but not limited to, Zou. R. , J. Med Chem. 1997, 40, 802. Scheme 4
  • Compounds of Formula X can be made from amino alcohols, Formula XI, by protecting the amine with a suitable protecting (P) under conditions known by those skilled in the art.
  • the alcohol can be oxidized to the aldehyde under conditions known in the art; such as but not limited to tetrapropylammonium perruthenate and N-methyl morpholine N-oxide in acetonitrile .
  • the amino alcohols that are not commercially available can be synthesized by methods known in the art and are exemplified by, but not limited to, Berg et . al . , J. Med. Chem. 1998, 41, 1934, Larrow et. al., Che tracts.
  • Formula XII Alternatively, compounds of Formula II can be synthesized by coupling compounds of Formula A with amino epoxides, Formula XII, as described in Scheme 6. It is understood that the chemistry is shown for only one A group of Formula I and that similar transformations may be preformed on other A groups.
  • the reaction can be preformed in an inert solvent such as, but not limited to, DMF, DMSO, or acetonitrile at room temperature to the reflux temperature of the solvent.
  • the amino protecting group (P) can then be removed under conditions known in the art.
  • the amino epoxides that are not commercially available can be synthesized by methods known in the art and are exemplified by, but not limited to, Luly et. al . , J. Or ⁇ . Chem. 1985, 50, 4515.
  • the reaction can be preformed in an inert solvent such as, but not limited to, DMF, 2-butanone, or acetonitrile at room temperature to the reflux temperature of the solvent.
  • the amino protecting group (P) can then be removed under conditions known in the art.
  • Intermediates of Formula XIII that are not commercially available can be synthesized by methods known in the art.
  • Formula XIX can be deprotected under conditions well known to one skilled in the art. Cyclization can achieved under dehydrating condition well known in the literature and exemplified by, but not limited to, Pearlman, W. M. Or ⁇ . Syn . 1969, 49, 75. The bicycliclactam, Formula XX, can then be reduced to the bicyclicamine of Formula A under conditions well known in the art such as, but not limited to, borane in THF at reflux.
  • isoquinoline ring systems may be synthesized by the intramolecular and intermolecular Diels-Alder routes depicted in Scheme 12 (see for example, W. Oppolzer et al . Helv. Chim. Acta. 1976, 59, 1186-1202; Neth. Appl . 75 03,392, 9/30/75 by Sandoz, Ltd.) .
  • the symbol P can be hydrogen or a protecting group such as benzyl, trifluoroacetyl, etc., or E or E-Y in precursor or final form. It to be understood that appropriate functionality may be present in Formula A,
  • n are in each case independently 1,2 p is 0 or 1
  • octahydroisoindoles, decahydroisoquinolines and related bicyclic systems may be synthesized by an intramolecular Diels-Alder reaction (see for example S. F. Martin, et al . , J. Or ⁇ . Chem. 1983, 48, 5170-5180; Carmosin, et al . , US 5,508,424, issued 4/16/96 to Ortho Pharmaceutical Corp.) as shown in Scheme 13.
  • n are in each case independently 1,2
  • a cyclic anhydride of Formula XXXI which is commercially available or can be easily synthesized by methods familiar to one skilled in the art is reacted with benzylamine to yield imide XXXII.
  • Deprotonation with a strong non-nucleophilic base such as LDA or KHMDS in an inert solvent such as ether or THF followed by quenching with a benzyl bromide, chloride, iodide, tosylate, mesylate, or triflate, yields a benzylated imide which can be reduced to cyclic amine XXXIII.
  • Deprotection yields a cyclic amine of Formula A.
  • n are in each case independently 1,2
  • DMF was added in a 6 hour period a mixture of ⁇ , ⁇ '- dibromo-o-xylene (23 g, 87.13 mmol) and n- benzylmaleimide (5 g, 26.71 mmol) in 50 mL DMF, as well as six portions of zinc dust (lg, 15.30 mmol) .
  • the mixture was stirred at room temperature for 20 hours, over which time a homogeneous solution was observed.
  • the mixture was poured into 1 L water, and 10 mL of concentrated hydrochloric acid was added. The solids were removed by filtration, and the filtrate was extracted with three 500 mL portions of ethyl acetate.
  • a solution of aluminum chloride (0.55 g, 4.2 mmol) in 5 ml of diethyl ether was added to a 1 M lithium aluminum hydride solution (10 mL, 10 mmol) in diethyl ether at 0° C, causing a white solid to precipitate.
  • the mixture was stirred at 0° C for 20 minutes, then cis-N-benzyl-1, 2,3, 4-tetrahydro-2 , 3- naphthalenedicarboximide was added neat (0.58 g, 2.2 mmol) .
  • the mixture was allowed to come to room temperature and stirred for 30 minutes, then brought to reflux for 90 minutes.
  • the mixture was cooled to 0° C, and the excess aluminum hydrides were destroyed using the Steinhardt procedure (see Fieser and Fieser, Reagents for Organic Synthesis; John Wiley & Sons, Inc.: New York, NY, 1967; p. 584.).
  • the resulting filtrate was diluted with 200 mL water, acidified with 1 N hydrochloric acid, and extracted with methylene chloride.
  • the methylene chloride was stripped, the residue was taken up in 1 N sodium hydroxide, and the mixture was extracted with chloroform.
  • the combined extracts were dried over sodium sulfate, and stripped to an amber oil.
  • the vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for an additional 3 days. TLC of the mixture showed that the reaction was still incomplete, and so the same amounts of palladium hydroxide and hydrochloric acid were added, the vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for an additional 6 days.
  • the mixture was filtered through celite, and the cake was rinsed with methanol. The filtrate was stripped, the residue was taken up in 20 mL of 1 N sodium hydroxide, and the aqueous was extracted with ethyl acetate.
  • Part A Preparation of N- (3-phenylallyl) -allylamine .
  • Step A Preparation of 3- (4-fluorophenyl) -3-hydroxy-l- propene .
  • Step B Preparation of 1- (4-fluorophenyl) -3-chloro-l- propene .
  • a gas dispersion tube was immersed in a solution of 3- (4-fluorophenyl) -3 -hydroxy-1-propene (1.0 g, 6.57 mmol) in 50 mL of toluene. Hydrochloric acid gas was bubbled through this solution for 10 min, causing a slight exotherm and a brown color. The tube was removed and the solution was diluted with 100 mL of ethyl acetate. This solution was washed with water, brine, dried over sodium sulfate and concentrated to 0.9 g of a brown oil as product.
  • Step A Preparation of ethyl 4- oxocyclohexanecarboxylate.
  • Step B Preparation of ethyl 4- (N, N- di (phenylmethyl ) amino) cyclohexanecarboxylate
  • Step D Preparation of ethyl 4-amino-l- (4- (fluorophenyl) methyl) cyclohexane-1-carboxylate
  • Step F Preparation of N- ( t-butoxycarbonyl) -1- (4- fluorophenyl) methyl) -3-azabicyclo [2.2.2] octane
  • reaction solution Upon cooling to 23 °C, the reaction solution was basified to pH 9.0-10.0 with 12.5 M aqueous sodium hydroxide . The aqueous layer was then extracted with ethyl acetate (4 x 60 mL) , and the combined organic layers were concentrated in vacuo to a colorless oil. The oil was dissolved in tetrahydrofuran (100 mL) at 23 °C and to the solution was added di-t- butyl dicarbonate (210 mg, 0.94 mmol).
  • Step G Preparation of 1- (4- (fluorophenyl ) methyl) -3- azabicyclo [2.2.2] octane hydrochloride
  • N- ( -butoxycarbonyl) -1- (4- fluorophenyl ) methyl) -3-azabicyclo [2.2.2] octane 270 mg, 0.85 mmol
  • 4 M hydrogen chloride in dioxane 50 mL
  • the reaction was concentrated to give 1- (4- (fluorophenyl) methyl) -3- azabicyclo [2.2.2] octane hydrochloride (220 mg, 100%) as a viscous yellow oil.
  • Step H Preparation of N-3 - [N' - ( -butoxycarbonyl) -3 - aminopropyl] -1- (4- (fluorophenyl) methyl) -3- azabicyclo [2.2.2] octane
  • the reaction was poured into IN aqueous hydrogen chloride (100 mL) , and the resulting mixture was basified to pH 9.0-10.0 with 12.5 M aqueous sodium hydroxide.
  • the basic layer was extracted with ethyl acetate (3 x 70 mL) , and the combined organic layers were washed with saturated aqueous sodium chloride (70 mL) , dried over sodium sulfate, and concentrated in vacuo .
  • Step J Preparation of N- (3-acetylphenyl) -N' - [3- [1- [ (4- fluorophenyl) methyl] -3-azabicyclo [2.2.2] oct-2- yl] propyl] urea hydrochloride.
  • Step C Preparation of 6- (4- (fluorophenyl) methyl) -2- azabicyclo [2.2.2] octane acetate.
  • Step D Preparation of enantiomeric mixture of ( 1S, AR, 6S) -N- ( -butoxycarbonyl) -6- (4- (fluorophenyl) methyl) -2-azabicyclo [2.2.2] octane and ( 1R, AS, 6R) -N- (t-butoxycarbonyl) -6- (4- ( fluorophenyl) methyl) -2-azabicyclo [2.2.2] octane and enantiomeric mixture of (15, AR, 6R) -N- ( -butoxycarbonyl) - 6- (4- (fluorophenyl) methyl) -2-azabicyclo [2.2.2] octane and ( IR, AS, 65) -N- ( -butoxycarbonyl) -6- (4- (fluorophenyl) methyl) -2-azabicyclo [2.2.2] octane
  • aqueous layer was extracted with ethyl acetate (3 x 70 mL) , and the combined organic layers were washed with saturated aqueous sodium chloride (50 mL) , dried over sodium sulfate, and concentrated in vacuo .
  • Step G Preparation of (15, 41?, 65) -2- (3 -aminopropyl) -6- (4- (fluorophenyl) methyl) -2-azabicyclo [2.2.2] octane dihydrochloride and (11?, 45, 61?) -2- (3 -aminopropyl) -6- (4- (fluorophenyl)methyl) -2-azabicyclo [2.2.2] octane dihydrochloride.
  • Step H Preparation of N- (3-acetylphenyl) -N'- [3- [ (15, 41?, 65) -6- [ (4-fluorophenyl) methyl] -2- azabicyclo [2.2.2] oct-2-yl] propyl] urea and N- ( 3 - acetylphenyl ) -N' - [ 3 - [ (11?, 45, 61?) -6- [ (4- fluorophenyl) methyl] -2-azabicyclo [2.2.2]oct-2- yl] propyl ] urea .
  • Step I Preparation of N- (3-acetylphenyl) -N'- [3- [ (15, 41?, 65) -6- [ (4-fluorophenyl) methyl] -2- azabicyclo [2.2.2 ] oct-2-yl] propyl] urea hydrochloride and N- (3-acetylphenyl) -N' - [3- [ (11?, 45, 61?) -6- [ (4- fluorophenyl) methyl] -2-azabicyclo [2.2.2] oct-2- yl] propyl] urea hydrochloride.
  • Step A Preparation of N- ( -butoxycarbonyl) -3- [ (4- fluorophenyl) ethylene] -8-azabicyclo [3.2.1] octane.
  • the reaction was maintained at reflux conditions for 60 hrs prior to being quenched with saturated aqueous ammonium chloride (30 mL) .
  • the layers were separated, and the aqueous layer was washed with ethyl acetate (3 x 30 mL) .
  • Step B Preparation of N- ( -butoxycarbonyl) - (3-exo) -3 - [ (4-fluorophenylmethyl] -8-azabicyclo [3.2.1] octane and N- ( -butoxycarbonyl) - (3-endo) -3- [ (4-fluorophenylmethyl] -8- azabicyclo [3.2.1] octane .
  • Step D Preparation of N- (benzyloxycarbonyl) -[ (25) -2- [ [ (3-exo) -3- [ (4-fluorophenyl) methyl] -8- azabicyclo [3.2.1] oct-8-yl] methyl] - (11?) -1-amino- cyclohexane.
  • the resulting white suspension was stirred for 12 hr and then added to aqueous IN hydrogen chloride (30 mL) .
  • the aqueous layer was basified with aqueous 12.5 ⁇ sodium hydroxide (3 mL) , and the layers were separated.
  • the aqueous layer was extracted with ethyl acetate (3 x 40 mL) , and the combined organic layers were washed with saturated aqueous sodium chloride (10 mL) and dried over sodium sulfate.
  • Step E Preparation of (25) -2- [[ (3-exo) -3- [ (4- fluorophenyl) methyl] -8-azabicyclo [3.2.1] oct-8- yl] methyl] - (11?) -1-amino-cyclohexane diacetate .
  • Step F Preparation of N- (3-acetylphenyl) -N' -[ (25) -2- [ [ (3-exo) -3- [ (4-fluorophenyl) methyl] -8- azabicyclo [3.2.1] oct-8-yl] methyl] - (21?) -1-cyclohexyl] urea
  • Example 17 N- (3-acetylphenyl) -N' - ⁇ 3- [ (IS, 5R, 6R) -6- (4- fluorophenyl) -3-azabicyclo [3.2.0]hept-3-yl]propyl ⁇ urea and N- (3-acetylphenyl) -N' - ⁇ 3- [ (IR, 5S, 6S) -6- (4- fluorophenyl) -3-azabicyclo [3.2.0] hept-3-yl]propyl ⁇ urea.
  • Table 1 contains representative examples of the present invention. Each entry in the table is intended to be paired with each formulae at the start of the table. For example, entry 1 in Table 1 is intended to be paired with a-h. TABLE 1
  • Cell lines for expressing the receptor of interest include those naturally expressing the chemokine receptor, such as EOL-3 or THP-1, those induced to express the chemokine receptor by the addition of chemical or protein agents, such as HL-60 or AML14.3D10 cells treated with, for example, butyric acid with interleukin-5 present, or a cell engineered to express a recombinant chemokine receptor, such as CHO or HEK-293.
  • chemical or protein agents such as HL-60 or AML14.3D10 cells treated with, for example, butyric acid with interleukin-5 present
  • a cell engineered to express a recombinant chemokine receptor such as CHO or HEK-293.
  • blood or tissue cells for example human peripheral blood eosinophils, isolated using methods as described by Hansel et al . , J. Immunol. Methods, 145, 105- 110 (1991), can be utilized in such assays.
  • the compound of the present invention have activity in binding to the CCR-3 receptor in the aforementioned assays.
  • activity is intended to mean a compound demonstrating an IC50 of 10 ⁇ M or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity.
  • a general binding protocol is described below.
  • CCR3-Receptor Binding Protocol Millipore filter plates (#MABVN1250) are treated with 5 ⁇ g/ml protamine in phosphate buffered saline, pH 7.2, for ten minutes at room temperature. Plates are washed three times with phosphate buffered saline and incubated with phosphate buffered saline for thirty minutes at room temperature.
  • binding buffer (0.5% bovine serum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI 1640 media) with or without a test concentration of a compound present at a known concentration is combined with 50 ⁇ l of 125-1 labeled human eotaxin (to give a final concentration of 150 pM radioligand) and 50 ⁇ l of cell suspension in binding buffer containing 5xl0 5 total cells.
  • Cells used for such binding assays can include cell lines transfected with a gene expressing CCR3 such as that described by Daugherty et al . (1996), isolated human eosinophils such as described by Hansel et al .
  • the utility of the compounds in accordance with the present invention as inhibitors of the migration of eosinophils or cell lines expressing the chemokine receptors may be demonstrated by methodology known in the art, such as the chemotaxis assay disclosed by Bacon et al., Brit. J. Pharmacol., 95, 966-974 (1988).
  • the compound of the present invention have activity in inhibition of the migration of eosinophils in the aforementioned assays.
  • activity is intended to mean a compound demonstrating an IC50 of 10 ⁇ M or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity.
  • a human eosinophil chemotaxis assay protocol is described below.
  • 5-micron filters in place are warmed in a 37°C incubator prior to assay.
  • Freshly isolated human eosinophils isolated according to a method such as that described by Hansel et al . (1991), are suspended in RPMI 1640 with 0.1% bovine serum albumin at 1 x 10 6 cells/ml and warmed in a 37°C incubator prior to assay.
  • a 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovine serum albumin is warmed in a 37°C incubator prior to assay.
  • the eosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1 with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or without a dilution of a test compound that is at two fold the desired final concentration. These mixtures are warmed in a 37°C incubator prior to assay.
  • the filter is separated from the prewarmed Neuroprobe chemotaxis chamber and the eotaxin/compound mixture is placed into a Polyfiltronics MPC 96 well plate that has been placed in the bottom part of the Neuro Probe chemotaxis chamber.
  • the approximate volume is 370 microliters and there should be a positive meniscus after dispensing.
  • the filter is replaced above the 96 well plate, the rubber gasket is attached to the bottom of the upper chamber, and the chamber assembled.
  • a 200 ⁇ l volume of the cell suspension/compound mixture is added to the appropriate wells of the upper chamber.
  • the upper chamber is covered with a plate sealer, and the assembled unit placed in a 37°C incubator for 45 minutes. After incubation, the plate sealer is removed and all remaining cell suspension is aspirated off.
  • the chamber is disassembled and, while holding the filter by the sides at a 90-degree angle, unmigrated cells are washed away using a gentle stream of phosphate buffered saline dispensed from a squirt bottle and then the filter wiped with a rubber tipped squeegee.
  • the filter is allowed to completely dry and immersed completely in Wright Giemsa stain for 30-45 seconds.
  • the filter is rinsed with distilled water for 7 minutes, rinsed once with water briefly, and allowed to dry. Migrated cells are enumerated by microscopy.
  • Mammalian chemokine receptors provide a target for interfering with or promoting immune cell function in a mammal, such as a human.
  • Compounds that inhibit or promote chemokine receptor function are particularly useful for modulating immune cell function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, infection by pathogenic microbes (which, by definition, includes viruses) , as well as autoimmune pathologies such as the rheumatoid arthritis and atherosclerosis.
  • an instant compound which inhibits one or more functions of a mammalian chemokine receptor may be administered to inhibit (i.e., reduce or prevent) inflammation or infectious disease.
  • a mammalian chemokine receptor e.g., a human chemokine receptor
  • one or more inflammatory process such as leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited.
  • eosinophilic infiltration to inflammatory sites e.g., in asthma or allergic rhinitis
  • inflammatory sites e.g., in asthma or allergic rhinitis
  • the compound of the following examples has activity in blocking the migration of cells expressing the CCR-3 receptor using the appropriate chemokines in the aforementioned assays.
  • activity is intended to mean a compound demonstrating an IC50 of 10 ⁇ M or lower in concentration when measured in the aforementioned assays. Such a result is also indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity.
  • an instant compound which promotes one or more functions of the mammalian chemokine receptor e.g., a human chemokine
  • an immune or inflammatory response such as leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • eosinophils can be recruited to combat parasitic infections.
  • treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for an instant compound which promotes one or more functions of the mammalian chemokine receptor if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or the delivery of compound in a manner that results in the misdirection of the migration of cells.
  • mammals including but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species.
  • the subject treated in the methods above is a mammal, male or female, in whom modulation of chemokine receptor activity is desired.
  • Modulation as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism.
  • Diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic cellulitis (e.g..
  • eosinophilic pneumonias e.g., Loeffler's syndrome, chronic eosinophilic pneumonia
  • eosinophilic fasciitis e.g., Shulman's syndrome
  • delayed-type hypersensitivity ILD
  • interstitial lung diseases e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus , ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis
  • drug allergies e.g., to penicillin, cephalosporins
  • eosinophilia-myalgia syndrome due to the ingestion of contaminated tryptophan, insect sting allergies
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis
  • diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
  • cytokine-induced toxicity e.g., septic shock, endotoxic shock
  • polymyositis e.g., septic shock, endotoxic shock
  • dermatomyositis e.g., HIV.
  • Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms) ; (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis) ; trematodes (flukes) (Schistosomiasis,
  • Clonorchiasis cestodes (tape worms) (Echinococcosis , Taeniasis saginata, Cysticercosis) ; visceral worms, visceral larva migraines (e.g., Toxocara) , eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larva migraines (Ancylostona braziliense, Ancylostoma caninum) .
  • the compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory, infectious and immunoregulatory disorders and diseases .
  • treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for promoters of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells.
  • the instant invention may be used to evaluate the putative specific agonists or antagonists of a G protein coupled receptor.
  • the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors.
  • the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition or as a reference in an assay to compare its known activity to a compound with an unknown activity.
  • compounds according to the present invention could be used to test their effectiveness.
  • such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving the aforementioned diseases.
  • the compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors.
  • Combined therapy to prevent and treat inflammatory, infectious and immunoregulatory disorders and diseases including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
  • the present compounds may be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumor necrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, a phosphodiesterase inhibitor, or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, interferon alpha and the like.
  • an anti-inflammatory or analgesic agent such
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist , simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine , naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine; and antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine .
  • a pain reliever such as caffeine, an H2-antagonist , simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, e
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compound of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) integrin antagonists such as those for selectins, ICAMs and VLA-4; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyprohepta
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective doses of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds are administered to a mammal in a therapeutically effective amount.
  • therapeutically effective amount it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines .
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-pheno1 , polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance .
  • water a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • saline aqueous dextrose (glucose)
  • glycols such as propylene glycol or polyethylene glycols
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are suitable stabilizing agents.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. Mack Publishing Company, a standard reference text in this field.
  • a large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • Soft Gelatin Capsules 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
  • the capsules should be washed and dried. Tablets
  • Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystallme cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. Injectable
  • a parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized. Suspension
  • An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mL of vanillin.
  • a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
  • the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anticoagulant in an amount of about 1 to 5 milligrams per dosage unit.
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
  • one active ingredient may be enteric coated.
  • enteric coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
  • HPMC hydroxypropyl methylcellulose
  • the polymer coating serves to form an additional barrier to interaction with the other component.

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Abstract

La présente invention décrit des modulateurs de CCR de la formule (I): A-E-NR<1>-G, ou des formes de sels de ceux-ci acceptables sur le plan pharmaceutique, utiles dans la prévention de maladies inflammatoires telles que l'asthme et d'autres maladies allergiques.
EP00973508A 1999-10-15 2000-10-13 Amines bicyliques et tricycliques en tant que modulateurs de l'activite du recepteur de chemokine Withdrawn EP1220840A2 (fr)

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AU1201101A (en) 2001-04-30
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